Prolonged T-cell immunodeficiency following HLA- incompatible hematopoietic stem cell transplantation (HSCT) represents a major obstacle hampering the more widespread use of this approach. Strategies to fasten T-cell reconstitution in this setting are highly warranted as opportunistic infections and an increased risk of relapse account for high rates of morbidity and mortality especially during early month following this type of HSCT. We have implemented a feeder free cell system based on the use of the notch ligand DL4 and cytokines allowing for the in vitro differentiation of human T-Lymphoid Progenitor cells (HTLPs) from various sources of CD34+ hematopoietic stem and precursor cells (HSPCs). Co- transplantion of human T-lymphoid progenitors (HTLPs) and non- manipulated HSPCs into immunodeficient mice successfully accelerated the reconstitution of a polyclonal T-cell repertoire. This review summarizes preclinical data on the use of T-cell progenitors for treatment of post- transplantation immunodeficiency and gives insights into the development of GMP based protocols for potential clinical applications including gene therapy approaches. Future clinical trials implementing this protocol will aim at the acceleration of immune reconstitution in different clinical settings such as SCID and leukemia patients undergoing allogeneic transplantation. Apart from pure cell-therapy approaches, the combination of DL-4 culture with gene transduction protocols will open new perspectives in terms of gene therapy applications for primary immunodeficiencies.
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The study was funded by the French National Institute of Health and Medical Research (INSERM), a European Research Council grant (ERC Regenerative Therapy, 269037), a European Union FP7 grant (CELL-PID, 261387), a European Union H2020 grant (SCIDNet, 666908), Imagine Institute, a Clinical Research Hospital Program (PHRC) (Ministry of Health and Social Affairs), an INCA-Plan Cancer grant (2009–2013) and a public grant overseen by the French National Research Agency (ANR) as part of the program “Investissements d’Avenir” (reference: ANR-10-IAHU-01). LS was funded by Imagine Institute. KM was funded by a China Scholarship Council (CSC). EE was funded by an INSERM-Plan Cancer fellowship. CR was funded by postdoctoral scholarships from the Deutsche Forschungsgemeinschaft (DFG). TT was funded by the Fund for Scientific Research Flanders (FWO Vlaanderen research projects G0B2913N). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publication of this supplement was sponsored by Gilead Sciences Europe Ltd, Cell Source, Inc., The Chorafas Institute for Scientific Exchange of the Weizmann Institute of Science, Kiadis Pharma, Miltenyi Biotec, Celgene, Centro Servizi Congressuali, Almog Diagnostic.
Conflict of interest
MC and IA-S own equity in Smart Immune and hold two patents in this area, about the in vitro process of production of T-cell progenitors. KM is co-inventor of patent WO 2018/146297 A1, Methods for generating T-cells progenitors. The remaining authors declare that they have no conflict of interest.
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André, I., Simons, L., Ma, K. et al. Ex vivo generated human T-lymphoid progenitors as a tool to accelerate immune reconstitution after partially HLA compatible hematopoietic stem cell transplantation or after gene therapy. Bone Marrow Transplant 54, 749–755 (2019). https://doi.org/10.1038/s41409-019-0599-9